Natural resistance to hemopoietic allografts, in particular F1 hybrid resistance to parental grafts, represents one of the most puzzling immunological phenomena. The resistance is genetically specific, characterized by a noncodominant mode of inheritance, and major histocompatibility complex (MHC)-controlled. The effector mechanism is mediated by natural killer (NK) cells, and hence radio-resistant and preexisting. These properties are unique, and not easily reconciled with the contemporary concepts of cellular immunology and transplantation genetics. The long- term objective of this research project is to elucidate the immunogenetic, cellular, and ultimately molecular mechanisms underlying the natural resistance. This application proposes an approach towards a molecular understanding of the cell surface target structures that are recognized in F1 hybrid resistance to parental H-2b/Hh-1b hemopoietic grafts. Studies are designed primarily to test the hypothesis that the target structures for hybid resistance are oligosaccharides. Clones of lymphoma cells lacking these determinants will be selected 1) specifically by resistant F1 hybrid hosts in vivo and 2) nonspecifically in vitro by selecting variants with altered cell surface oligosaccharides. Somatic cell hybridization will be used to study the nature of genetic lesions in the variant clones. The effect of selected glycosylation inhibitors on the expression of Hh-1b determinants will be tested and Hh-1b positive and negative clones biochemically compared. These studies are essential for a better understanding of the role of NK cells in normal hemopoiesis, in immune surveillance for hemopoietic neoplasms, and in bone marrow allograft failure in man.